HIV infection in male genital organs has not been a major focus of research and is not understood. The antigenic properties of male germ cells create the need for immune protection, the mechanisms of which are unclear but are believed to be a combination of anatomic barriers against routine leukocyte traffic and specialized mechanisms of inhibiting leukocyte mediated immune responses. Hence, HIV infection of semen producing organs is a complex process which may result in sequestered, immune privileged foci of virus infection, the parameters of which may change during the course of disease progression. This possibility has profound significance with respect to viral genetic drift and effective treatment strategies. Some semen producing organs, such as testis and prostate are resistant to penetration by many pharmacologic agents, creating the potential to eradicate foci of HIV infection in blood, but not semen compartments. Preliminary studies in this and other laboratories have shown that viral burden in semen is discordant with blood, supporting the view that semen is not simply another body fluid which will reflect HIV infection in blood and lymph compartments. The goal of the proposed research is to test the hypothesis that semen may be a unique, distinct reservoir of HIV infection. The work has been divided into the following specific aims: 1) Compare viral burden in semen and blood in longitudinal studies of HIV infected men. We will quantify free virus, test for infectivity of free virus and cells, and determine the frequency of infected cells in matched specimens of blood and semen collected twice a year for a period of 5 years. 2) Determine the principal source of semen leukocytes and whether or not they routinely equilibrate with peripheral blood. We will characterize lymphocyte populations in germ-cell depleted semen from men with known interruptions in the genital tract such as congenital absence of the vas deferens and vasectomy. 3) Determine if the presence of sperm influences leukocyte populations in germ cell compartments and semen. We will determine lymphocyte populations in semen specimens from men with germ cell arrest, such as men with "Sertoli only" syndrome and cancer survivors. In addition, we will study the influence of germ cell presence on lymphocyte migration into the epididymis of unilaterally castrated mice. The results of these studies will begin to define for the first time the possible sources of HIV host cells in semen and identify the organ targets for antiviral therapy.